Allogeneic stem cell transplantation (alloSCT) is a well-established therapy for hematologic malignancies. Despite its curative potential, alloSCT is limited by the lack of human leukocyte antigen (HLA)-matched donors for most patients and by significant toxicity, especially GVHD and opportunistic infection. We have used high dose, post-transplantation cyclophosphamide (Cy) in two existing clinical trials to enable partially HLA-mismatched alloSCT after nonmyeloablative conditioning and to eliminate the requirement for prolonged pharmacologic immunosuppression after HLA-matched alloSCT. Both of these trials have shown remarkably low incidences of acute and chronic GVHD, a low incidence of serious opportunistic infection, and low treatment-related mortality. The central objectives of this proposal are to characterize the effects of high-dose, post-transplantation Cy on alloreactivity and immune reconstitution after alloSCT, and to use high-dose, post-transplantation Cy to suppress graft rejection and graft-versus-host disease (GVHD) after lethal conditioningand partially HLA-mismatched alloSCT. Our studies are based on the hypothesis that post-transplantation Cy selectively induces tolerance in proliferating, alloreactive T cells while sparing resting T cells responsible for immunity to infection; i.e. post-transplantation Cy induces selective invivo allodepletion. Accordingly, we propose the following specific aims: (1) Characterize the mechanism(s) of post-transplantation Cy-induced tolerance, (2) Characterize the effects of post-transplantation Cy on the reconstitution of T cells and antigen-specific T cells, and (3) Conduct a phase II trial of myeloablative, haploidentical BMT with T cell replete grafts and post-transplantation Cy. The overall career goal of the candidate is to become an independent translational investigator in clinical immunotherapy. Immediate career goals are to (1) develop expertise in immunology based laboratory assays and (2) develop expertise in the design and conduct of a clinical trial to treat patients with advanced hematologic malignancies. A mentoring committee comprising seasoned investigators will guide the candidate through a series of phased research endeavors in a rich, academic environment strongly committed to the candidate. RELEVANCE (See instructions): This proposal utilizes a novel regimen of post-transplant immunosuppression to minimize transplant-related complications. The aims proposed are' crucial for establishing partially HLA-mismatched BMT as a first-line alternative donor option and identifying a new gold standard for GVHD prophylaxis. This proposal is the foundation for future novel and widely applicable immunotherapies.